A novel in vitro three‐dimensional bioprinted liver tissue system for drug development

Abstract

Despite efforts to improve the ability to identify the toxicity of therapeutic compounds, the attrition rate for both experimental and approved drugs remains very high. Cardio‐ and hepatotoxicity remain primary reasons for late stage failures and post‐market withdrawals. Therefore more robust human, in vitro models of these organ systems are needed. We have developed a bioprinted three‐dimensional (3D) liver system that captures several key features of in vivo tissue, in a multi‐well format suitable for drug screening. Using NovoGenTM bio‐printing technology we have fabricated 3D liver constructs containing architecturally‐ and physiologically‐relevant features for two hepatic cell lines and primary hepatocytes, within standard multi‐well culture plates. Bioprinted, 3D hepatic neotissues were further enhanced in complexity with the addition of endothelial and hepatic stellate cells. Biochemical studies demonstrate that several critical liver functions are present including cytochrome P450 activity. Tight junction protein expression was observed throughout the 3D tissue. Analysis of cell death and proliferation following in vitro maturation revealed the constructs were viable. These results demonstrate a flexible bioprinting method to rapidly fabricate multi‐cellular 3D liver constructs in a multi‐well format enabling both drug screening and interrogation of liver biology.